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Don Francisco Fernández de la Cueva was born at Barcelona into one of the most aristocratic families of Spain, as the eldest viable adult male from the third marriage of his father, the 7th duke, (1575–1637). His father was "one of the toughest, most rigorous, and successful of the viceroys of Catalonia...and had specialized in hte [sic] suppression of disorder."[1] Don Francisco's first marriage to Doña Antonia, a powerful "de Toledo-Beaumont" family woman, was childless. Further, the only offspring of the duke's marriage with Ana María de Padilla, his second wife, deceased before 1614, also from a powerful family, Beltran, died at age 16 before 1617. In his 3rd marriage, the heirless duke, married to a woman surnamed Enríquez de Cabrera y Colonna, who produced 10 children; his wife survived him some 21 years.[citation needed]

Francisco, the eldest male, entered military service when very young. He served in the cavalry [2] in Flanders. Later, as general of cavalry, he fought in the defense of Tortosa and in the siege of Barcelona in 1650. One feature of his career would be also his Ambassadorial activities in the Germanic countries.

Because of the war with England, he feared an invasion of Spanish territories in the New World. Because of this he strengthened the defenses of Veracruz and San Juan de Ulúa on the east coast of New Spain. He also sent arms and munitions to Jamaica, Cuba and Florida.

He increased trade with the Philippines, Siam and Cochinchina, sending mercury, saltpeter and other mineral products. He ordered the resumption of the minting of gold coins (suspended by Viceroy Antonio de Mendoza). He collected the royal rents with care, and sent back to Spain large quantities of silver. He reinforced the Armada de Barlovento, which guarded the coast and shipping. He ordered the construction in Campeche of new ships for the coastal and overseas trade. He also repaired the aqueduct supplying Mexico City with water.

The viceroy accelerated the construction of the new cathedral of Mexico City, visiting it every afternoon, climbing the scaffolding, and giving monetary rewards to the workers. During a visit to the cathedral on 12 March 1660, a 19-year-old soldier in the viceroy's guard, Manuel Ledesma y Robles of Madrid, attacked the viceroy with a sword. The viceroy survived. Justice was swift for his attacker, who was quickly tried, then dragged around the city and back to the Plaza Mayor, where he was hanged the next day.

The city of Alburquerque (now spelled Albuquerque), in what is now New Mexico, was founded on February 7, 1706 (not 1660) under his son's direction. He granted land to more than 100 Spanish families there.

The writers of this period attributed to his government a strong encouragement for the development of the sciences and the arts. His palace was considered a model of elegance and good taste.

He left New Spain for Madrid in September, 1660. Thereafter he was named lieutenant general of marines. He also served as ambassador extraordinary to Vienna to accompany Infanta Margaret Theresa of Spain, daughter of King Philip IV of Spain, when she married her uncle, Leopold I, Holy Roman Emperor. In 1668 Fernández de la Cueva was named viceroy of Sicily, where he remained two years. In 1674 the King appointed him as his Mayordomo mayor, chief of his Household.